Stroke is defined as a pathological condition in which impairment of consciousness and neurologic symptom(s) are acutely induced by a cerebrovascular disorder, such as intracerebral hemorrhage and cerebral infarction, and according to a report published by the Ministry of Health, Labor and Welfare, stroke was the third popular cause of death in Japan in 2004. Even if a patient is lucky enough to escape the death, the aftereffects are often so serious that the quality of life of the patient is greatly impaired. In addition, an onset of stroke is associated with a high risk of its recurrence. Accordingly, stroke has become an issue of public concern.
A relevance of the stroke with hypertension has been known for a long time, and blood pressure control has been advocated and practiced by using various antihypertensives to prevent onset or recurrence of the stroke. As a result, the mortality from stroke of intracerebral hemorrhage type certainly decreased. However, with the westernization of diet and the resulting increase of the patients suffering from so-called “lifestyle-related diseases” such as diabetes, hyperlipidemia and hypertension, the types of stroke in Japan has changed, and today, stroke in Japan consists of about 80% by cerebral infarction, about 15% by intracerebral hemorrhage, and about 5% by subarachnoid hemorrhage. As the cerebral infarction is increasing in accordance with the westernization of diet, attentions have brought on the hyperlipidemia among the lifestyle-related diseases, and it has been advocated that arteriosclerotic diseases, namely, myocardial infarction, cerebral infarction, and the like, be prevented by improving cholesterol, especially the low density lipoprotein-cholesterol (LDL-C), also known as “bad cholesterol”.
With this as a backdrop, various clinical trials (e.g. KLIS, PATE, J-LIT) using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (HMG-CoA RI), the so-called “statin agent” having strong hypocholesterolemic action, have been conducted in Japan, and a certain efficacy of statin in preventing onset of cerebral infarction has been suggested. However, for efficacy in secondary prevention of the stroke, namely, prevention of its recurrence, results have not so far been gratifying.
Other exemplary compounds having the action of improving hyperlipidemia are polyunsaturated fatty acids. The polyunsaturated fatty acid is defined as a fatty acid including two or more carbon-carbon double bonds in one molecule, and the polyunsaturated fatty acids are categorized based on the position of the double bond into ω-3 fatty acid, ω-6 fatty acid, and so on. The ω-3 polyunsaturated fatty acids include α-linolenic acid, icosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), and the ω-6 polyunsaturated fatty acids include linoleic acid, γ-linolenic acid, and arachidonic acid. Polyunsaturated fatty acids are derived from natural products, and exhibit various actions including antiarteriosclerotic action, platelet aggregation inhibitory action, hypolipidemic action, antiinflammatory action, antitumor action, and central action, and with their high degree of safety, they are incorporated in various foods, and sold as health foods or drugs.
It has been reported that the mortality of patients with history of myocardial infarction was decreased by administration of a mixture of ethyl ester of EPA (EPA-E) and ethyl ester of DHA (DHA-E), the ω-3 polyunsaturated fatty acids, for 3.5 years (International Patent Publication No. WO 00/48592). However, this reference does not disclose or suggest whether EPA-E or DHA-E prevents the onset and/or recurrence of stroke.
It has been suggested that administration of a fish oil containing EPA and DHA should prevent brain damages in patients exhibiting atherosclerosis of the artery which feeds blood to the brain (International Patent Publication No. WO 03/92673). However, this reference histologically observed plaques in carotid artery of the patients who have undergone carotid endarterectomy, but fails to demonstrate effects on preventing brain damages and/or the onset of the stroke.
Recently, based on the results of animal experiments and small scale clinical findings, many large scale clinical trials have been planned and performed in order to examine whether various drugs proven to have some effects of improving the lifestyle-related diseases are capable of preventing arteriosclerotic diseases in human. So far, however, the results have not been as expected, and especially the secondary prevention of the stroke is still in a state of trial and error.
High purity EPA-E is commercially available in Japan in the trade names of Epadel and Epadel S (manufactured by Mochida Pharmaceutical Co., Ltd.) as a therapeutic drug for hyperlipidemia. There has been reported that when such high purity EPA-E is orally administered at a dose of 600 mg per administration and 3 times a day immediately after meals (when triglyceride (TG) is abnormal, the dose was increased up to 900 mg per administration and 3 times a day, depending on the degree of the abnormality), the serum total cholesterol (T-Cho) concentration was reduced by 3 to 6%, and the serum TG was reduced by 14 to 20% (Drug Interview Form “EPA preparation, Epadel capsule 300”, revised in July, 2002 and February, 2004, version 21 issued in December, 2004; pp. 21-22). There has also been reported in the American College of Cardiology 2005 Annual Meeting that, based on such action, the high purity EPA-E would be expected to have an effect of improving cardiovascular events of hyperlipidemia patients, and its use in combination with statin was effective for inhibiting cardiac events in a large scale clinical trial (Medical Tribune, issue of Nov. 17, 2005, Feature Article Part 3, pp. 75-76; Circulation Vol. 112 (No. 21), pp 3362-3363, 2005). However, these publications do not disclose or suggest that EPA-E prevents onset and/or recurrence of the stroke.